Previous reports documenting the essentially identical spectra of activity of ceftizoxime, cefotaxime, and ceftriaxone prompted our hospital formulary committee to replace the latter two drugs with ceftizoxime on the basis of cost differences. However, we subsequently observed that every one of 60 isolates of Streptococcus pneumoniae tested was less susceptible to ceftizoxime than to either cefotaxime or ceftriaxone. The difference between minimal inhibitory concentrations (MICs) was greatest for strains moderately or fully resistant to penicillin, which at our institution represent approximately 32% of all isolates of S. pneumoniae. Ten isolates with cefotaxime and ceftriaxone MICs of 2.0-6.0 micrograms/mL had ceftizoxime MICs of > or = 256 micrograms/mL. Time-kill kinetic studies assessing bactericidal activity confirmed the diminished activity of ceftizoxime against penicillin-resistant isolates of S. pneumoniae. Ceftizoxime should not be used to treat proven or suspected pneumococcal infection in areas where resistance to penicillin is prevalent.